期刊
PROTEIN & CELL
卷 9, 期 10, 页码 879-889出版社
SPRINGEROPEN
DOI: 10.1007/s13238-018-0510-2
关键词
ZNRF3; -TRCP; Wnt; ubiquitination; CKI
类别
资金
- China Scholarship Council (CSC) [201606120241]
- National Research Service Award T-32 training grant
- National Natural Science Foundation of China [31571323]
- NIH [RO1-GM057603]
- Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [P30 HD-18655]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P30HD018655] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM057603] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [K01AG052627] Funding Source: NIH RePORTER
Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing -TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of -catenin by -TRCP, ZNRF3 is ubiquitinated by -TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for -TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by -TRCP in a context-dependent manner where -TRCP negatively regulates Wnt signaling by targeting -catenin, and positively regulates Wnt signaling by targeting ZNRF3.
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